Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
  • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to the use of partially known N-alkylated 1,4-dihydropyridinedicarboxylic acid esters as a hemorheological medicament, new active substances and processes for their preparation, in particular their use as medicaments for acute and chronic ischemic diseases which are associated with microcirculation disorders. This effect can occur in the peripheral as well as in the cerebral vascular system.
• 1,4-dihydropyridinedicarboxylic acid esters have a calcium-antagonistic or calcium-agonistic effect and can therefore be used as agents which influence the circulation [cf. DOS 25 06 987; DE 22 10 667].
• EP 240 828 describes 1,4-dihydropyridines which reduce blood pressure and have hemorheological properties.
• the compounds according to the invention show an unforeseeable, valuable spectrum of pharmacological activity.
• Blood pressure neutrality is determined on the following models typical of dihydropyridines: In SH rats after po administration by measurement on the tail artery (Riva Rocci method) and on anesthetized Wistar rats after iv administration (bloody via catheter in carotid artery). Compounds that reduce blood pressure up to a maximum of 20% of the initial value in both test models with the specified dose are referred to as blood pressure neutral.
• the distance between the therapeutic dose and the onset of blood pressure is at least a factor of 10, usually a factor of ⁇ 30, in particular ⁇ 100.
• ischemic diseases such as intermittent claudication, myocardial infarction, brain infarction, as well as reperfusion damage and shock.
• the invention also relates to new 1,4-dihydropyridinedicarboxylic acid esters, which are listed below: 1,2,6-trimethyl-4- (1-naphthyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dibutyl ester 1,2,6-Trimethyl-4- (4-fluorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester 1,2,6-Trimethyl-4- (2-cyanophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dipropyl ester 1,2,6-Trimethyl-4- (4-nitrophenyl) -1,4-dihydro-pyridine-3,5-dicarboxylic acid dibutyl ester 1,2,6-Trimethyl-4- (4-trifluoromethylphenyl) -1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester 1,2,6-
• Particularly preferred compounds are the 1,4-dihydropyridinedicarboxylic acid esters, the phenyl ring of which is simply substituted in the para position by fluorine, bromine or by the CF3 group.
• Some of the compounds according to the invention exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
• the invention relates to both the antipodes and the racemic forms as well as the diastereomer mixtures.
• the racemic forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner (cf. E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).
• Water or organic solvents which do not change under the reaction conditions are suitable as solvents. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric acid triamide, or glacial acetic acid, dimethyl sulfoxide, acetonitrile or pyridine.
• alcohols such as methanol, ethanol, propanol, isopropanol
• ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether
• amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric acid triamide, or glacial acetic acid, dimethyl sulfoxide,
• reaction temperatures can be varied within a wide range. In general, one works between + 10 ° C and + 150 ° C, preferably between + 20 ° C and + 100 ° C, especially at the boiling point of the respective solvent.
• the reaction can be carried out at normal pressure, but also at elevated or reduced pressure. Generally one works at normal pressure.
• the ratio of the substances involved in the reaction is arbitrary. In general, however, one works with molar amounts of the reactants.
• the substances according to the invention are preferably isolated and purified in such a way that the solvent is distilled off in vacuo and the residue, which is optionally obtained in crystalline form only after ice cooling, from a suitable solvent recrystallized. In some cases it may be necessary to purify the compounds of the invention by chromatography.
• aldehydes of the general formula (IV) used as starting materials are known or can be prepared by known methods [DOS 21 65 260; 24 01 665; TD Harris, GP Roth, J. Org. Chem. 44 , 2004 (1979); WJ Dale, HE Hennis, J. Am. Chem. Soc. 78: 2543 (1956); Chem. Abstr. 59 , 13929 (1963)].
• ⁇ -ketocarboxylic acid esters of the general formulas (V) and (Va) used as starting materials are known or can be prepared by known methods [D. Borrmann in Houben Weyl's "Methods of Organic Chemistry” Vol. VII / 4, 230 (1968); Y. Oikawa, K. Sugano, O. Yonemitsu, J. Org. Chem. 43 , 2087 (1978)].
• ⁇ -aminocrotonic acid esters of the general formulas (III) and (IIIa) used as starting materials are known or can be prepared by known methods [DOS 2 228 377; FA Glickman, AC Cope, J. Am. Chem. Soc. 67 , 1017 (1945)].
• reactive acid derivatives are: activated esters, hydroxysuccinimide esters, acid imidazolides, acid halides, mixed anhydrides or the reaction in the presence of cyclohexylcarbodiimide.
• alkylating agents in the process for example, (C1-C8) alkyl halides, sulfonic acid esters or substituted or unsubstituted (C1-C6) dialkyl sulfates, preferably methyl iodide, p-toluenesulfonic acid ester or dimethyl sulfate can be used.
• the alkylation is carried out in the solvents listed above at temperatures from 0 ° C. to + 150 ° C., preferably at room temperature to + 100 ° C. under normal pressure.
• carbodiimides such as cyclohexylcarbodiimide or 1-cyclohexyl-3- [2- (N-methyl-morpholino) ethyl] carbodiimide-p as activating reagents for the preparation of the reactive acid derivatives include toluenesulfonate or N-hydroxyphthalimide or N-hydroxybenztriazole in the presence of dicyclohexylcarbodiimide mentioned as examples.
• the separation of the diastereomer pairs is carried out according to known methods such as column chromatography, fractional crystallization or Craig distribution [for Craig distribution see, for example, "Distribution method in the laboratory", E. Hecher, Verlag Chemie GmbH, Weinheim, Bergstr. (1955)].
• the new and the known compounds according to the invention show an unforeseeable, valuable pharmacological spectrum of action.
• Filtration of erythrocytes through 5 ⁇ m sieve pores is an established method for determining the deformability of erythrocytes.
• the cells are sheared in normal buffer for 30 minutes so that the calcium concentration increases intracellularly and the flexibility is reduced.
• the biophysical interactions of erythrocytes relevant for blood circulation can be examined in glass capillaries (diameter 20-30 ⁇ m).
• the resulting viscosity depends on the condition of the cells. When calcium is loaded, the viscosity increases.
• the percentage improvement in viscosity based on damaged but untreated control is given at 0.7 Pa.
• the test dose is 10 ⁇ 8 g / ml.
• the microcirculation can be observed directly in the model of the hamster cheek pouch. Measured variables are the Leukocyte adhesion as well as vessel diameter and erythrocyte speed. Adhesion was quantified under ischemic and non-ischemic test conditions. Adhesion is quantified in the area of small venules under non-ischemic conditions, in small arterioles under ischemic conditions (10 min circulation stop). The results of the control tests are given as 100%. The test dose chosen is 0.1 mg / kg iv, the results are a decrease in% of the control.
• the table shows that compared to model II, the distance between the therapeutic and blood pressure effects (i.v.) is at least 100.
• the new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
• the therapeutically active compound should be present in a concentration of approximately 0.5 to 90% by weight of the total mixture be, ie in amounts that are sufficient to achieve the specified dosage range.
• the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.
• the application is carried out in the usual way, preferably orally or parenterally, in particular perlingually or intravenously.
• solutions of the active ingredients can be used using suitable liquid carrier materials.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• Vascular Medicine (AREA)
• Urology & Nephrology (AREA)
• Epidemiology (AREA)
• Hydrogenated Pyridines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
• Lubricants (AREA)

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Cited By (14)

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• 1990
  • 1990-04-11 DE DE4011695A patent/DE4011695A1/de not_active Withdrawn
• 1991
  • 1991-03-30 DE DE59102788T patent/DE59102788D1/de not_active Expired - Fee Related
  • 1991-03-30 DK DK91105115.9T patent/DK0451654T3/da active
  • 1991-03-30 EP EP91105115A patent/EP0451654B1/fr not_active Expired - Lifetime
  • 1991-03-30 AT AT91105115T patent/ATE111079T1/de active
  • 1991-03-30 ES ES91105115T patent/ES2063998T3/es not_active Expired - Lifetime
  • 1991-04-04 US US07/680,454 patent/US5234935A/en not_active Expired - Fee Related
  • 1991-04-08 CA CA002040062A patent/CA2040062A1/fr not_active Abandoned
  • 1991-04-08 JP JP3101762A patent/JP3012352B2/ja not_active Expired - Lifetime
  • 1991-04-08 NZ NZ237722A patent/NZ237722A/en unknown
  • 1991-04-08 IL IL9779691A patent/IL97796A/en not_active IP Right Cessation
  • 1991-04-09 AU AU74253/91A patent/AU642992B2/en not_active Ceased
  • 1991-04-09 PT PT97300A patent/PT97300B/pt not_active IP Right Cessation
  • 1991-04-09 FI FI911700A patent/FI101377B1/fi active
  • 1991-04-10 IE IE120091A patent/IE64452B1/en not_active IP Right Cessation
  • 1991-04-10 ZA ZA912652A patent/ZA912652B/xx unknown
  • 1991-04-10 TW TW080102712A patent/TW197423B/zh active
  • 1991-04-10 KR KR1019910005710A patent/KR0180741B1/ko not_active Expired - Fee Related
  • 1991-04-11 HU HU911184A patent/HUT59905A/hu unknown
• 1993
  • 1993-05-21 US US08/065,503 patent/US5432185A/en not_active Expired - Fee Related
• 1995
  • 1995-06-22 HU HU95P/P00334P patent/HU211313A9/hu unknown

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